Chromatin protein complexes involved in gene repression in lamina-associated domains

Lamina-associated domains (LADs) are large chromatin regions that are associated with the nuclear lamina (NL) and form a repressive environment for transcription. The molecular players that mediate gene repression in LADs are currently unknown. Here, we performed FACS-based whole-genome genetic screens in human cells using LAD-integrated fluorescent reporters to identify such regulators. Surprisingly, the screen identified very few NL proteins, but revealed roles for dozens of known chromatin regulators. Among these are the negative elongation factor (NELF) complex and interacting factors involved in RNA polymerase pausing, suggesting that regulation of transcription elongation is a mechanism to repress transcription in LADs. Furthermore, the chromatin remodeler complex BAF and the activation complex Mediator can work both as activators and repressors in LADs, depending on the local context and possibly by rewiring heterochromatin. Our data indicate that the fundamental regulators of transcription and chromatin remodeling, rather than interaction with NL proteins, play a major role in transcription regulation within LADs. Lamina-associated domains (LADs) are chromatin regions at the inner nuclear membrane that form a repressive environment for transcription. Here, a haploid genetic screen revealed that chromatin protein complexes such as NELF, BAF, and Mediator, but not nuclear lamina components, are the main regulators of transcriptional repression in LADs.Chromatin proteins rather than nuclear lamina proteins control repression in LADs.Regulators of transcriptional elongation, such as NELF complex, contribute to repression of transcription in LADs.The chromatin remodeler BAF and the Mediator complex can both repress and activate transcription in LADs. A haploid genetic screen identifies regulators of transcription and chromatin remodeling involved in gene repression in lamina-associated domains.